Reactivation of Early-Life Stress-Sensitive Neuronal Ensembles Contributes to Lifelong Stress Hypersensitivity

Abstract

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser-extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.Significance StatementEarly-life stress enhances sensitivity to stress later in life, yet the mechanisms of such stress sensitization are largely unknown. Here, we show that neuronal ensembles in corticolimbic brain regions remain hypersensitive to stress across the lifespan, and quieting these ensembles during experience of adult stress rescues stress hypersensitivity.

Early-life stress alters postnatal chromatin development in the nucleus accumbens

“…Both male and female samples were collected from each group at each age. For both Std and ELS groups, approximately 10% of nuclei in the NAc were tagged and captured ( Figure 1E ), consistent with previous count estimates of experience-activated cells by immunohistochemistry (Balouek et al, 2023). We then performed ATAC-sequencing (assay for transposase-accessible chromatin; (Buenrostro et al, 2013) in both tagged and untagged cell populations to characterize and compare open chromatin regions across treatment conditions and cell populations ( Supplemental Table 1 ).…”

“…Given previous findings that ELS-activated cells in the NAc are preferentially reactivated by stress (Balouek et al, 2023), we examined chromatin profiles in ELS-activated and non-activated cell populations separately. To permanently tag and isolate these separate cell populations, we utilized double transgenic ArcCreER T2 x Sun1-sfGFP-Myc mice (Figure 1A) in which transgene expression is both neuronal activity-and ligand-dependent (Denny et al, 2014;Balouek et al, 2023). ELS occurred in a stress sensitive window from postnatal day P10-17 as previously described (Peña et al, 2017(Peña et al, , 2019a.…”

“…In children, ELS alters development and connectivity of the ventral striatum, and changes in NAc activity are associated with blunted reward processing, anhedonia, and heightened response to stressors (Hanson et al, 2015(Hanson et al, , 2016(Hanson et al, , 2018Kirshenbaum et al, 2024). At a cellular level, ensembles of NAc neurons initially activated by experience of ELS are hyper-reactive to stress across the lifespan, contributing to stress sensitivity in mice (Balouek et al, 2023). Interestingly, ELS-activated neurons are not hyperactive in the absence of additional stress.…”

Lifelong molecular consequences of high Glucocorticoids exposure during development

“…Early life stress (ELS) affects healthy development and aging as well as susceptibility to psychiatric disorders in humans [1][2][3][4] . Studies in humans and animals suggest ELS may increase risk for psychiatric diseases such as depression by inducing hypersensitivity to future stress exposure [5][6][7][8] . However, mechanism by which ELS sensitizes responses to future stress responses in adulthood remains poorly understood.…”

Gas5 regulates early life stress-induced anxiety and spatial memory

“…Maternal separation, a well-established model of early-life stress, has been extensively studied to investigate the long-term consequences of adverse early life events during this critical period of brain function and behaviour (Taylor et al, 2010;Korosi et al, 2012). Stress due to maternal separation (MS) in rodents leads to anxiety-like behaviours in adulthood as characterized by heightened fear, avoidance, and stress sensitivity (Banqueri et al, 2017;Lundberg et al, 2020;Balouek et al, 2023). The ventral hippocampus, a key brain area affected by MS (Dimatelis et al, 2014;Marais et al, 2009), has been shown to regulate emotions (Jimenez et al, 2018;H.…”